The subject invention relates generally to the field of medical devices and methods for monitoring physiological parameters of the body and, more particularly, such devices and methods which are capable of monitoring on a long-term basis various physiological constituents present in the bloodstream.
Six million Americans have diabetes mellitus. On some schedule, all of these patients need to monitor their blood glucose levels to keep their disease under control. This monitoring is done by urine testing, which indirectly reflects blood glucose, by intermittent blood glucose tests by venipuncture or blood glucose monitoring by finger prick and strip analysis. There are many inaccuracies associated with urine testing, and many patients are reluctant to do an adequate number of blood tests because of the pain involved. As a result many diabetics do not maintain good glucose control.
Growing evidence proves that poor glucose control is a causative factor in development of the secondary complications of diabetes. These secondary complications take a great toll in morbidity and mortality. Twenty to twenty five per cent of End Stage Renal Disease is caused by diabetes. About 5000 diabetics become blind annually, and about 20,000 require amputations. Diabetes increases the risk of cardiovascular disease and diabetics also suffer from painful and sometimes disabling neuropathies.
The monetary cost for the treatment of the secondary complications of diabetes is extremely high. The current cost of dialysis for End Stage Renal Disease is about $25,000 per patient annually. The annual hospital costs for amputations is presently about $250 million. Disability payment and rehabilitation services for blind diabetics cost about $45 million annually.
The best prospect for reducing the morbidity and mortality of diabetes lies in technological developments which will provide better blood glucose control. Insulin infusion pumps and finger-stick home blood glucose monitoring are steps in that direction. The development of an implantable glucose monitoring device would make home blood glucose monitoring simpler, less painful and more acceptable for the diabetic population. This would be a significant step toward improving blood glucose control since it would provide much more information than available with any current method of glucose monitoring. The greatly increased knowledge of blood glucose levels obtained by an implantable monitoring system would permit analysis of the basic kinetic parameters of insulin in each patient, e.g. insulin sensitivity and half life. Also, a reliable long term glucose sensor could be combined with automatic insulin infusion systems already available to form an "artificial pancreas". With such a device it would be possible to maintain blood glucose within normal limits with little patient intervention.
The only hospital use instrument which has been on the market for constant blood glucose monitoring is the Biostator, manufactured by Miles Laboratories, Inc., Elkhart, Ind. This instrument constantly withdraws blood to monitor blood glucose concentration and infuses insulin in response to the blood glucose level. This type of instrument is very expensive and is therefore available in only a relatively few hospitals. Further, because the Biostator device requires a continuous flow of blood without return to the patient there is a limit on the amount of time over which the instrument can be used, and there are also problems and risks involved with the vascular access.
A number of different approaches have been taken to develop an implantable glucose sensor. Most approaches utilize a chemical reaction of glucose which actually consumes the glucose in the process of measuring it. Thus they are sensitive to the mass transfer coefficient of glucose to the sensor. Fibrous tissue formation around the sensor changes the calibration of the device. Secondly, those with enzyme components suffer degradation of the enzyme after several days of use.
Enzymatic glucose electrodes utilize an immobilized enzyme, glucose oxidase, which reacts selectively with glucose, in conjunction with an ion selective electrode which measures the decrease of one of the reactants (0.sub.2) as reported in Gough D.A. et al.: Progress toward a potentially implantable, enzyme-based glucose sensor. Diabetes Care 5:190-198, 1982, or the increase of one of the products (H.sub.2 O.sub.2). The change in potential or current at the electrode can be used to make kinetic measurements or the steady state current or potential can be used for equilibrium measurements as disclosed in Guilbault G.G.: Enzymatic glucose electrodes. Diabetes Care 5:181-183, 1982.
An electroenzymatic sensor disclosed in Clark et.al.: Implanted electroenzymatic glucose sensors. Diabetes Care 5:174-180, 1982 involves the enzymatic oxidation of glucose by glucose oxidase and the production of H.sub.2 O.sub.2. The H.sub.2 O.sub.2 is measured voltametrically at a Platinum electrode. The current produced by H.sub.2 O.sub.2 is directly proportional to the glucose in blood, plasma or tissue fluid in the 0 to 100 mg/dl region. At higher glucose concentrations there is a non-linear increase in current with increasing glucose concentration.
A glucose oxidase electrochemical sensor which detects the production of H.sub.2 O.sub.2 has been made in a needle form and has functioned up to 3 days in subcutaneous tissue as reported in the publication Shichiri M. et al.: Use of wearable artificial pancreas to control diabetes. Progress in Artificial Organs 782-787, 1983. When this sensor was coupled with a micro-computer and an insulin infusion system, glucose control was achieved which was superior to that achieved with conventional treatment. After three days there was a fixation of proteins and blood cells to the membrane of the electrode, resulting in diminished function.
An O.sub.2 sensitive enzymatic glucose sensor which can be inserted into an arterio-venous shunt is disclosed in the following publication: Kondo T. et al.: A miniature glucose sensor, implantable in the blood stream. Diabetes Care 5:218-221, 1982. This sensor can function 200 hours with a 10% loss in activity. Another publication, Ikeda et al.: Comparison of O.sub.2 electrode type and H.sub.2 O.sub.2 electrode type as a glucose sensor for the artificial B-cell. Prog. in Artificial Organs 773-777, 1983 compared the in vivo function of the O.sub.2 sensor with a H.sub.2 O.sub.2 electrode in a vascular access and found the O.sub.2 electrode responded better to changes in blood glucose. However, this sensor is impractical because of the amount of vascular surgery necessary to install the shunt.
Another approach to a glucose sensor is the catalytic electrode sensor, which is based on the electrochemical oxidation of glucose on a platinum electrode. Such sensors are reported in the following publications: Lerner H. et al.: Measurement of glucose concentration with a platinum electrode. Diabetes Care 5:229-237, 1982; Lewandowski J.J. et al.: Amperometric glucose sensor: Short-term in vivo test. Diabetes Care 5:238-244, 1982. The applied voltage is varied and the current response is measured. The current-voltage curves vary with glucose concentration. Other substances, such as amino acids and urea, can affect the output of this sensor, but use of a compensated net charge method of evaluating the response improves the sensitivity. Another problem is change in the loss in catalytic activity over time. Overall, this type of sensor has not demonstrated the selectivity or sensitivity necessary for a useful glucose sensor.
Several other technologies for glucose sensors depend on chemical or physical properties of glucose such as its affinity for lectins described in Schultz J.S. et al.: Affinity sensor: A new technique for developing implantable sensors for glucose and other metabolites, Diabetes Care 5:245-253, 1982, its optical rotation in solution described in Rabinovitch B. et al.: Non-invasive glucose monitoring of the aqueous humor of the eye: Part I. Measurement of very small optical rotations, Diabetes Care 5:254-258, 1982; and March W. F., et al.: Non-invasive glucose monitoring of the aqueous humor of the eye: Part II. Animal studies and the scleral lens, Diabetes Care 5:259-265, 1982, or its osmotic effect, Janle-Swain E. et al.: A hollow fiber osmotic glucose sensor, Diabetes 33: Supp. 1, 176A, 1984. These approaches do not consume glucose, but rather depend on the concentration of glucose at the device site reaching an equilibrium with tissue glucose. None of these devices have proven to be totally satisfactory.
In the Schultz et al. study, a monitoring system is disclosed which operates based on the ability of glucose and a fluorescein-labeled dextran to bind competitively to the lectin Concanavalin A (Con A). Con A can be bound to the inside of a hollow fiber through which glucose can diffuse. Fluorescein labeled dextran is added to the inside of the fiber. The amount of fluorescein labeled dextran is added to the inside of the fiber. The amount of fluorescein-labeled dextran displaced from the Con A is measured by an argon laser fiber optic system. This system has responded to differences in glucose concentration in vitro, but less than the theoretical response was obtained. In vitro tests have demonstrated that the Con A can remain bound to the fibers for eight days.
Another study, Shichiri M. et. al.: Telemetry glucose monitoring device with needle type glucose sensor: A useful tool for blood monitoring in diabetic individuals, Diabetes Care 9:298-301, 1986, supports that measurement of glucose in the subcutaneous tissue does provide an adequate indication of blood glucose. This study discloses a correlation in diabetic patients between tissue glucose and blood glucose, with correlation coefficients ranging from 0.89 to 0.95. This work indicates a five minute delay between changes in blood glucose and subcutaneous tissue glucose, with tissue glucose being 6 to 22% lower than blood glucose. This decrease in subcutaneous glucose versus blood glucose is due to the metabolism of glucose by subcutaneous tissue. The level of glucose which is obtained depends upon the metabolic rate of the subcutaneous tissue, the blood flow, the degree of fibrous tissue in the space, and the rate of fluid transfer across the capillary wall.
The goal of all of these studies was to develop sensors for permanent subcutaneous placement. Currently there does not exist an implantable glucose sensor which will function for an extended period of time in vivo. There are a number of sensors which function in vitro and some which function well for a few days in vivo, but none have proved effective over long periods of time. Measurement of blood glucose is done by diabetic patients at home by the finger-stick method. A drop of blood is placed on a paper strip impregnated with glucose oxidase and a chromophore. The color change produced by the glucose in the blood is determined visually or with a small hand held reflectance meter. In hospitals blood glucose may be measured at the bedside by the same finger-stick and strip method used by patients at home or venous blood samples may be analyzed automatically in the laboratory using glucose analyzers which are usually based on spectrophotometric or electrocatalytic analysis methods.